The present invention relates to crystalline 4′-epidaunorubicin hydrochloride and a process for the production thereof.
Anthracyclines comprise a large group of naturally occurring bioactive compounds. Several anthracyclines are used in clinics as anticancer chemotherapeutic drugs. Examples of clinically important substances are daunorubicin, doxorubicin, idarubicin, epirubicin, pirarubicin, aclarubicin, caminomycin, and zorubicin. Anthracyclines can be produced either by chemical synthesis or by fermenting microorganisms. They are used as such (for example, aclarubicin, daunorubicin and caminomycin) or are semi-synthetic derivatives of other anthracyclines (such as epirubicin, idarubicin, doxorubicin, pirarubicin, and zorubicin). Anthracyclines are effective against leukemia and various solid cancerous tumors. Worldwide, the most used anthracyclines are doxorubicin and epirubicin. Epidaunorubicin is the key-intermediate in the synthesis of epirubicin.
U.S. Pat. Nos. 4,112,076; 4,345,068; 4,861,870; 5,945,518; and 5,874,550 disclose the preparation of epirubicin hydrochloride and its use as an anticancer agent.
Currently, the major method for purifying 4′-epidaunorubicin hydrochloride is amorphous precipitation thereof from a solution by addition of an antisolvent. Usually, in this method, a basic solution of epidaunorubicin is treated with methanolic hydrochloric acid to adjust the pH value in a range between 2 and 5, and subsequently 4′-epidaunorubicin hydrochloride is precipitated by addition of an ether.
U.S. Pat. No. 4,345,068 discloses precipitation of 4′-epidaunorubicin hydrochloride from a chloroform extract using methanolic hydrochloric acid. Although referred to as “crystallization,” this process does not produce crystalline, but amorphous 4′-epidaunorubicin hydrochloride.
Boivin et al., “Substitutions of allylic esters: preparation of 3-aminoglycals and their acid-catalyzed glycosidation. Use in the partial synthesis of glycosides of the anthracycline group,” Carbohydrate Research, 79 (2):193-204 (1980) disclose precipitation of 4′-epidaunorubicin hydrochloride from ethanol/ether. This process has also been found to produce amorphous, not crystalline 4′-epidaunorubicin hydrochloride.
Amorphous precipitation of 4′-epidaunorubicin hydrochloride, however, has the drawback that the precipitated 4′-epidaunorubicin hydrochloride is only purely soluble and often purified unsatisfactorily.